A single-nucleotide promoter region polymorphism (-108C/T) of the paraoxonase (PON1) gene had been suggested to influence an individual's susceptibility to coronary artery disease (CAD). No data is available on this polymorphism from India. One hundred seventy-eight healthy individuals and 204 angiographically proven CAD patients were recruited to get baseline data on the frequency distribution of the -108C/T polymorphism in normal people of Asian Indian ethnicity and its relation with the risk of CAD. Polymerase chain reaction followed by restriction fragment length analysis was used as the method for genotyping. Blood samples were used for DNA isolation. In the normal subjects, the genotypes were distributed as CT (43.26%) > CC (30.34%), >TT (26.4%). The allele frequency of the C allele was 0.52, and that of the T allele was 0.48. The patients showed a similar pattern, but the TT genotype was about two times more frequent in the controls than in patients. Odds ratios for developing CAD for individuals with CT, TT, and CT + TT genotypes were 0.89 (0.50-1.59), 0.56 (0.27-1.08), and 0.76 (0.44-1.29), respectively (at 95% confidence interval), when compared to CC homozygous people (age- and sex-adjusted, p = 0.114, all genotypes compared). This suggested a trend for the T allele as protective against CAD. This first report on the frequency distribution of the -108C/T polymorphism in people of Asian Indian ethnicity suggests that the normal distribution is similar to that observed for the Chinese, Japanese, and Latino people, but the disease association is unique. The TT genotype and the T allele which are widely found associated with the risk of CAD showed a protective trend in this study.